Restrictive Fluid Management for Liver Transplant Patients

(REFIL Trial)

Recruiting at 4 trial locations

Overseen By François-Martin Carrier, MD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Centre hospitalier de l'Université de Montréal (CHUM)

Disqualifiers: Acute liver failure, Severe renal failure, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

72 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests two methods for managing fluid levels during liver transplants in individuals with severe liver disease. The aim is to determine if a restrictive approach, which limits fluid intake to reduce complications, is more effective than a liberal approach, which provides more fluids to maintain blood flow. Patients with end-stage liver disease scheduled for a liver transplant may be suitable candidates, particularly if they have not experienced other major organ issues or certain severe conditions. The trial will examine how well doctors adhere to these methods and their impact on recovery within six months post-surgery. As an unphased trial, it offers patients the chance to contribute to significant research that could enhance liver transplant outcomes.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that carefully controlling the amount of fluid given during surgery, known as restrictive fluid management, can be safe for liver transplant patients. This method may help reduce complications like fluid overload, which can occur with excessive fluid administration.

Patients in earlier studies managed this careful fluid control well, without an increase in serious side effects compared to more relaxed fluid management. Some research even suggests that this approach can lead to better recovery after surgery by preventing extra fluid buildup and improving blood flow.

Overall, while researchers continue to study restrictive fluid management, early results suggest it is a safe option for liver transplant patients. It is important to consult with a doctor to receive the most personalized and up-to-date information for individual health needs. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about this trial because it explores how different fluid management strategies might improve outcomes for liver transplant patients. The restrictive fluid management approach is unique because it lowers splanchnic blood volume by combining phlebotomy with fluid restriction, which could reduce blood loss and fluid overload during surgery. On the other hand, the liberal fluid management strategy optimizes cardiac output by using fluid boluses, ensuring the patient maintains stable circulation during the operation. By comparing these approaches, researchers hope to identify which method offers better surgical outcomes and improved recovery for liver transplant patients.

What evidence suggests that this trial's fluid management strategies could be effective for liver transplant patients?

This trial will compare two fluid management strategies for liver transplant patients. Studies have shown that carefully controlling fluid amounts during surgery can reduce complications after liver transplants. Participants in the restrictive group will follow a low splanchnic blood volume restrictive fluid management strategy. This involves removing some blood at the start of surgery and returning it later, helping to maintain the patient's balance. Research indicates that using less fluid during surgery can lower the risk of lung problems afterward. One study suggested that this approach can lead to fewer issues compared to administering more fluids. The goal is to manage fluids carefully to avoid overload and improve recovery. Meanwhile, participants in the liberal group will receive an optimized cardiac output liberal fluid management strategy, focusing on optimizing cardiac output throughout the surgery. ^{3 4 5 6 7}

Who Is on the Research Team?

Francois-Martin Carrier, MD

Principal Investigator

Centre hospitalier université de Montréal

Are You a Good Fit for This Trial?

The REFIL trial is for adults over 18 years old who need a liver transplant due to end-stage liver disease (ESLD). It's not for those with acute liver failure, cancer without ESLD, retransplantation, amyloid neuropathy, severe kidney failure (GFR < 15), severe anemia (hemoglobin < 80 g/L), or hemodynamic instability.

Inclusion Criteria

I am 18 or older and getting a liver transplant for end-stage liver disease.

Exclusion Criteria

Patients with severe anemia (hemoglobin level < 80 g/L)

I have severe kidney failure or am on dialysis.

I require high doses of medication to maintain my blood pressure.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Intraoperative Treatment

Participants undergo liver transplantation with either a restrictive or liberal fluid management strategy

During surgery

Postoperative Follow-up

Participants are monitored for postoperative outcomes, including complications and graft function

30 days

Regular monitoring until hospital discharge

Extended Follow-up

Participants are monitored for long-term outcomes, including survival and quality of life

Up to 1 year

What Are the Treatments Tested in This Trial?

Interventions

• Low splanchnic blood volume Restrictive fluid management strategy
• Optimized cardiac output liberal fluid management strategy

Trial Overview This study compares two fluid management strategies during liver transplantation. One group receives a restrictive strategy with phlebotomy and limited fluids; the other gets a liberal strategy aiming to optimize cardiac output. The goal is to see which method leads to better outcomes.

How Is the Trial Designed?

Group I: Restrictive group: Low splanchnic blood volume Restrictive fluid management strategy Experimental Treatment 2 Interventions

The intervention group is targeted at lowering splanchnic blood volume using a phlebotomy and restricting fluid infusion, individualized to the physiological needs of this population and the distinct LT surgical phases. The strategy will first consist of performing a phlebotomy without fluid replacement at the start of surgery.We will combine it with fluid restriction to prevent excessive fluid administration and its effect on splanchnic blood volume and blood loss, combined with the effect of the phlebotomy, as well as to limit fluid overload, as previously reported. Fluid will be administered to compensate blood loss and treat severe hemodynamic instability.The phlebotomy will be transfused back at the beginning of the reperfusion phase where fluid management will be based on a goal-directed therapy (GDT) using either PPV or SV, as in the control group.

Group II: Liberal group: Optimized cardiac output liberal fluid management strategy Active Control 1 Intervention

The control group will receive a liberal intraoperative fluid management strategy optimizing cardiac output throughout the surgery. It will consist of administering 250 mL fluid boluses until SV stops to increase by more than 10% or until PPV is below 12%, a dynamic indicator of fluid responsiveness validated in many surgical populations, including ESLD patients undergoing a LT.This strategy is informed by data from recent clinical trials on benefits of GDT in major surgery, data on strategies used in major surgery, liver resection or LT and our survey on current practice.

Low splanchnic blood volume Restrictive fluid management strategy is already approved in Canada for the following indications:

Approved in Canada as Restrictive Fluid Management Strategy for:

• Liver Transplantation

Who Is Running the Clinical Trial?

Centre hospitalier de l'Université de Montréal (CHUM)

Lead Sponsor

Trials

389

Recruited

143,000+

Canadian Institutes of Health Research (CIHR)

Collaborator

Trials

1,417

Recruited

26,550,000+

Canadian Donation and Transplantation Research Program (CDTRP)

Collaborator

Trials

1

Recruited

70+

Canadian Perioperative Anesthesia Clinical Trial (PACT) Group

Collaborator

Trials

1

Recruited

70+

Published Research Related to This Trial

Restrictive fluid management strategies during liver transplant surgery did not show any significant impact on the incidence of acute kidney injury (AKI) or mortality, based on a systematic review of 7 randomized controlled trials and 29 observational studies.

However, these strategies were associated with reduced pulmonary complications, shorter duration of mechanical ventilation, and less blood loss, suggesting potential benefits in other postoperative outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Restrictive fluid management strategies and outcomes in liver transplantation: a systematic review. Carrier, FM., Chassé, M., Wang, HT., et al.[2021]

In a study of 532 adult liver transplant recipients, the use of vasopressors did not increase the risk of acute kidney injury (AKI) within 48 hours or 7 days post-surgery, suggesting they may be safe in this context.

However, higher fluid balance was linked to increased need for renal replacement therapy and lower survival rates in patients not receiving vasopressors, indicating that vasopressor use may alter the negative effects of fluid management on postoperative outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of intraoperative hemodynamic management on postoperative acute kidney injury in liver transplantation: An observational cohort study. Carrier, FM., Sylvestre, MP., Massicotte, L., et al.[2020]

In patients with liver cirrhosis undergoing liver transplantation, traditional volume loading methods may be ineffective and could worsen surgical bleeding due to splanchnic vasodilatation that diverts blood away from the systemic circulation.

Alternative volume therapy strategies, such as volume restriction or using vasoconstrictors, may be more effective in maintaining hemodynamic stability during surgery, although the optimal central venous pressure to avoid graft congestion post-reperfusion remains unclear.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Splanchnic and systemic circulation cross talks: Implications for hemodynamic management of liver transplant recipients. Mukhtar, A., Lotfy, A., Hussein, A., et al.[2021]

In a study of liver transplant recipients, fluid management guided by stroke volume variation (SVV) resulted in similar outcomes to traditional central venous pressure (CVP) monitoring, with no significant differences in blood loss, acute kidney injury (AKI), or survival rates at 30 days and 1 year.

The use of SVV as a decision-making tool for fluid management in liver transplant patients appears to be as effective as CVP, suggesting that both methods can be used interchangeably in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fluid management guided by stroke volume variation failed to decrease the incidence of acute kidney injury, 30-day mortality, and 1-year survival in living donor liver transplant recipients. Wang, SC., Teng, WN., Chang, KY., et al.[2019]

A restrictive fluid management strategy combined with acute normovolemic intraoperative hemodilution (ANIH) was found to be a safe technique for living donors undergoing liver transplantation, with no significant differences in postoperative renal and liver functions.

This approach led to a shorter hospital stay for patients (8.2 days vs. 10.1 days) and showed a trend towards reduced blood transfusion requirements, suggesting it may enhance recovery after surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of restrictive fluid management and acute normovolemic intraoperative hemodilution on transfusion requirements during living donor hepatectomy. Balci, ST., Pirat, A., Torgay, A., et al.[2008]

A low central venous pressure (CVP) fluid management strategy during liver transplantation resulted in increased rates of postoperative renal failure and higher 30-day mortality compared to a normal CVP strategy.

While the low CVP approach reduced blood transfusion requirements, it is not recommended for liver transplantation patients due to the associated risks of renal complications and mortality.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intraoperative fluid management during orthotopic liver transplantation. Schroeder, RA., Collins, BH., Tuttle-Newhall, E., et al.[2019]

In a study of 121 liver transplant patients, a cumulative positive fluid balance (FB) of over 10 liters in the first 4 days post-surgery was found to significantly increase the risk of acute kidney injury (AKI) and the need for renal replacement therapy (RRT).

While fluid overload did not directly affect mortality rates, other factors like liver function markers and the severity of the patient's condition were more closely linked to survival outcomes after liver transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cumulative positive fluid balance is a risk factor for acute kidney injury and requirement for renal replacement therapy after liver transplantation. Codes, L., de Souza, YG., D'Oliveira, RAC., et al.[2020]

This systematic review aims to evaluate the impact of restrictive versus liberal perioperative fluid management strategies on postoperative outcomes in liver transplant recipients, focusing on acute renal failure as the primary outcome and other complications and mortality as secondary outcomes.

The review will include randomized controlled trials and comparative studies, analyzing data from major medical databases to provide high-quality evidence that could inform future clinical practices and improve survival rates for liver transplant recipients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of perioperative fluid management on postoperative outcomes in liver transplantation: a systematic review protocol. Carrier, FM., Chassé, M., Wang, HT., et al.[2019]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05647733

Restrictive Fluid Management In Liver Transplantation ... Secondary endpoint: The secondary feasibility endpoints are a protocol adherence > 90%, a 30-day (or hospital discharge) and 6-month outcome measurement > 90%, ...

2. clinicaltrial.be clinicaltrial.be/en/details/174372?per_page=20&recruiting=1&enrolling_by_invitation=1&active_not_recruiting=1&not_yet_recruiting=0&completed=0&only_recruiting=0&only_eligible=0

Restrictive Fluid Management In Liver Transplantation (RE... The intervention group is targeted at lowering splanchnic blood volume using a phlebotomy and restricting fluid infusion, individualized to the ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/31556006/

Restrictive fluid management strategies and outcomes in ... We conducted a systematic review to evaluate the effects of restrictive perioperative fluid management strategies, compared with liberal ones, on postoperative ...

4. ctv.veeva.com ctv.veeva.com/study/restrictive-fluid-management-in-liver-transplantation-refil

Restrictive Fluid Management In Liver Transplantation (REFIL) The intervention group is targeted at lowering splanchnic blood volume using a phlebotomy and restricting fluid infusion, individualized to the ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4149738/

Restricted Crystalloid Fluid Therapy during Orthotopic Liver ... Restricted crystalloid fluid administration during orthotropic liver transplantation though decreased post-operative chance of pulmonary insufficiency, did not ...

6. clinicaltrial.be clinicaltrial.be/en/details/174372?per_page=100&recruiting=1&enrolling_by_invitation=0&active_not_recruiting=0&not_yet_recruiting=0&completed=0&only_recruiting=1&only_eligible=0

Restrictive Fluid Management In Liver Transplantation (RE... MAIN OBJECTIVE The main objective of the REFIL-1 pilot study is to establish the feasibility (recruitment, adherence, outcome measurement) ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4721990/

Modulation of splanchnic circulation: Role in perioperative ... This review highlights some potential benefits derived from modulating splanchnic circulation during the perioperative management of patients undergoing liver ...